A Comparative Analysis of Efficacy of Apatinib Combined with Transarterial Chemoembolization and Transarterial Chemoembolization Alone in the Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus

Background The treatment of hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) remains controversial due to the limited effect of sorafenib. The aim of the study was to investigate whether apatinib could improve the efficacy of transarterial chemoembolization (TACE) for patients with HCC complicated by PVTT. Methods The study included 109 patients with HCC and PVTT who received TACE combined with apatinib (TACE + apatinib) (53 patients) or TACE alone (56 patients) between June 2015 and January 2019. Propensity score matching (PSM) analysis was used to reduce the potential selection bias. Overall survival time (OS) and time to progression (TTP) were used to evaluate the efficacy of TACE + apatinib and TACE alone. Results Before PSM, TACE + apatinib significantly improved median TTP (7.0 vs. 3.0 months, P < 0.001) and median OS (15.0 vs. 7.0 months, P < 0.001) when compared with TACE alone. After PSM, the median TTP was significantly longer in the TACE + apatinib group, 6.0 months, than in the TACE alone group, 3.0 months (P < 0.001), and the median OS was significantly longer in the TACE + apatinib group, 14.0 months, than in the TACE alone group, 7.0 months (P < 0.001). Subgroup analysis revealed that, except for patients with Child–Pugh class B, the patients with or without extrahepatic metastases and with Child–Pugh class A had longer TTP and OS after the combined TACE + apatinib treatment than after TACE alone. Conclusion The combination of TACE + apatinib might be an effective and safe treatment for HCC patients with PVTT.


Introduction
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and results in 782,000 deaths annually [1]. Due to latent symptoms and limited screening, most HCC patients are diagnosed at an advanced stage of the tumor [2]. Portal vein tumor thrombus (PVTT), i.e., the invasion of the main portal veins and their branches, is the most common macrovascular invasion and represents one of the significant risk factors for poor HCC prognosis [3][4][5]. Since patients suffering from PVTT are typically in the advanced stages of HCC [6], traditional treatment options certain HCC patients with PVTT, especially those with preserved liver function and sufficient collateral blood flow in the vicinity of the blocked portal vein [10][11][12]. Based on the results of a meta-analysis, the time to progression (TTP) in patients with unresectable HCC treated by a combination of TACE with sorafenib was longer than in patients treated with TACE alone [13]. Recently, several studies documented that the combination of TACE and sorafenib as a strategy to treat HCC patients with PVTT provides greater benefits than sorafenib monotherapy [14,15].
Apatinib is a novel molecular inhibitor selectively targeting vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase. Although apatinib is similar to sorafenib, its binding affinity to VEGFR-2 is 10 times higher [16,17]. Apatinib was approved in China for the treatment of advanced or metastatic gastric cancer [18]. Additionally, apatinib exhibited better effects against HCC than sorafenib, both in vivo and in vitro [19]. e efficacy of inhibiting HCC growth and angiogenesis by apatinib was comparable to that of sorafenib but was associated with fewer adverse effects. A single-arm, open-label phase II clinical trial reported that apatinib showed a robust clinical effect in patients with advanced HCC, with a median OS of 13.8 months and a median progression-free survival (PFS) of 8.7 months [20].
Since VEGFR-2 plays a significant role in neovascularization after TACE [21], the combination of TACE and apatinib may improve the outcome of the treatment of advanced HCC due to selective inhibition of VEGFR-2. In fact, several studies revealed that patients with advanced HCC who underwent treatment with TACE and apatinib (TACE + apatinib) benefited more than patients treated by TACE alone [21][22][23]. Although these results are encouraging, these studies did not directly demonstrate an improvement in the survival of HCC patients with PVTT after apatinib administration. To date, there is a shortage of data that could provide evidence for the advantages of the TACE + apatinib combination treatment. erefore, we conducted a retrospective study to compare the efficacy and safety of TACE + apatinib with TACE alone in the treatment of HCC patients with PVTT.

Study Design and Patient Selection.
e diagnosis of HCC was based on the European Association for the Study of the Liver (EASL) criteria [24]. Computed tomography (CT) or magnetic resonance imaging (MRI) was used to diagnose PVTT and assess its location.
is study included 109 HCC patients with PVTT who underwent TACE + apatinib or TACE alone at our hospital between June 2015 and January 2019. Among them, 53 patients were treated with TACE + apatinib and 56 with TACE alone. A propensity score matching (PSM) was used to reduce the patient selection bias and balance the variables between the two treatment groups. e treatment selection was mostly based on the patient's preference. e safety and efficacy of the TACE + apatinib treatment were analyzed retrospectively and compared with TACE alone.
Approval for this retrospective study was obtained from our college ethics committee (UHCT-IEC-SOP-016-03-01). Informed consent was obtained from the patients before the first TACE procedure. e inclusion criteria were as follows: (1) diagnosis of HCC; (2) Child-Pugh class A or B; (3) Eastern Cooperative Group Performance Status (ECOG) score of ≤2 points; (4) PVTT by contrast-enhanced CT or MRI before the TACE procedure; and (5) platelet count ≥60 × 10 9 /L. e exclusion criteria were as follows: (1) the main portal vein completely blocked without collateral circulate; (2) Child-Pugh class C; (3) liver transplantation, liver resection, or local-regional therapies before the TACE procedure; and (4) sorafenib therapy, or systemic chemotherapy.

TACE Procedure and Apatinib Administration.
e TACE procedure and the protocol of apatinib were described in our prior studies [23,25]. Briefly, TACE was performed by operators who had at least 5 years of experience and utilized a transfemoral arterial access route with a micropuncture system by placing a 5-F vascular introducer (Cook, Bloomington, IN, USA). Celiac and superior mesenteric arteriographies were carried out to assess the arterial anatomy, tumor supplying vessels, and the patency of the portal vein. e tumor feeding arteries were selectively cannulated with a 3-F microcatheter. A 5-20 ml aliquot of lipiodol (Lipiodol Ultrafluido, Guerbet, France) was mixed with 10-40 mg doxorubicin hydrochloride (Hisun Pharmaceutical Co. Ltd., Zhejiang, China) to create an emulsion, and then 5-20 ml of the emulsion was injected into tumorfeeding arteries through the microcatheter, followed by supplement embolization with gelatin sponge particles (300-700 um, Cook Medical, Bloomington, IN, USA).
In the TACE + apatinib group, apatinib was taken orally 3-5 days after each TACE procedure at an initial dosage of 500 mg/day. e dosage of apatinib was adjusted according to the patient's tolerance to the drug. e adverse events of apatinib were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) [23]. If the adverse events were grade 3 or higher without effective control, the apatinib was reduced to 250 mg/day to relieve or eliminate the adverse events. If the adverse events (≥ grade 3) did not disappear after the dose adjustment, the administration of the drug was temporarily interrupted. e 250 mg/day dose was restored when the adverse events were alleviated or disappeared [23].

Follow-Up.
All patients were followed up until January 2020.
e follow-up included abdominal contrast-enhanced CT or MRI, and laboratory tests. e first follow-up was performed at the end of the fourth week after the first TACE procedure. A repeated TACE was needed when the recurrent tumor or residual lesions were found on imaging. Subsequent follow-up examinations were conducted every 2 months, starting 4 weeks after the first TACE procedure. Journal of Oncology

Definition and Assessments.
e review of medical records included CT, MRI, and laboratory data. Tumor response was evaluated using the modified Response Evaluation Criteria in solid tumors (mRECIST) [26]. e assessment of tumor response was carried out at the first month after the first TACE procedure and then every 2 months until the time of progression or death. Disease control rate (DCR) was defined as the portion of patients who achieved a complete response (CR), partial response (PR), and stable disease (SD) (CR + PR + SD) [26]. Objective response rate was defined as the portion of patients who achieved CR, PR (CR + PR) [22]. Overall survival (OS) and time to progression (TTP) were used to evaluate the efficacy of treatment. OS was defined as the time between the first TACE and the last follow-up or all-cause death. TTP was defined as the time from the first TACE to the onset of tumor progression. Adverse events were measured based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Classification of PVTT.
PVTT was classified into three types, including type I: tumor thrombus involving segmental branches of the portal vein or above; type II: tumor thrombus involving the right/left portal vein; and type III: tumor thrombus involving the main portal vein trunk based on Cheng's classification [27].
2.6. PSM Analysis. PSM analysis was conducted using the SPSS 24.0 software (IBM, Armonk, NY, USA). e baseline variables including age, neutrophil, lymphocyte, ALT, AST, hemoglobin, platelets, gender, HBV, type of PVTT, extrahepatic metastases, AFP, Child-Pugh, and ECOG were matched in our model. One-to-one matching without replacement was applied, and the value of the caliper was 0.2.

Statistical Analyses.
e statistical analyses were performed using the SPSS 24.0 software. Normally distributed data, nonnormally distributed data, and categorical variables are expressed as mean ± standard deviation, median (quartile range), and frequency (percentage), respectively. e Pearson x 2 test, correction x 2 test, Fisher's exact test, independent-samples t-test, and Mann-Whitney U test were used to compare the two groups. Kaplan-Meier curves and log-rank test were used to compare TTP and OS between two groups. Variables with the value of P < 0.10 at univariate analysis were entered into univariate Cox proportional hazards regression model analysis, which was used to identify risk factors affecting OS. P value <0.05 (two-tailed) was considered statistically significant.

Patient Population.
e study included 109 HCC patients with PVTT who received TACE + apatinib (N � 53) or TACE alone (N � 56). During the follow-up period, 40 (75.5%) deaths and 51 (96.2%) patients with tumor progression were observed in the TACE + apatinib group. In the TACE alone group, 52 (92.9%) deaths and 56 (100%) cases of tumor progression were observed. After the PSM analysis, 46 pairs of patients were matched (Figure 1). e baseline characteristics of the two groups did not show significant differences before and after PSM (Table 1).

Overall Survival Analyses.
Before PSM, the median OS was 15.0 months in the TACE-apatinib group and 7 months in the TACE alone group (P < 0.001) (Figure 2(a)). After PSM, the median OS was 14.0 months in the TACE-apatinib group and 7 months in the TACE alone group (P < 0.001) (Figure 3(a)).

Time to Progression Analyses.
Before PSM, the median TTP was 7.0 months in the TACE-apatinib group and 3.0 months in the TACE alone group (P < 0.001) (Figure 2(b)). After PSM, the median TTP was 6.0 months in the TACEapatinib group and 3.0 months in the TACE alone group (P < 0.001) (Figure 3(b)). e patients in the TACE-apatinib group had a longer TTP than in the TACE alone group before and after PSM. Table 2. e adverse events of hand-foot skin reactions, hypertension, and proteinuria in the TACEapatinib group were more common than those in the TACE group (all P < 0.05). However, the severe adverse events (grades ≥3) in the TACE-apatinib group were similar to those in the TACE group (all P < 0.05). e adverse events associated with the TACE procedure in the two groups are shown in Table 3. Before PSM, four adverse events were observed across four patients in the TACE-apatinib group. Four adverse events were also identified across four patients in the TACE alone group.

Prognostic Factors Associated with TTP and OS.
Univariate analysis and multivariate Cox regression analysis were performed to reveal prognostic factors for TTP and OS.

Subgroup Analyses.
e results of subgroup analyses are listed in Figure 4. For the patients with or without extrahepatic metastases, with Child-Pugh class A, the median TTP and OS in the TACE-apatinib group were significantly longer than in the TACE alone group. However, for patients with Child-Pugh class B, there was no significant difference in the efficacy of the treatment between the two groups.

Discussion
Patients with PVTT usually have an unsatisfactory OS due to the aggressive course of the disease, declining liver function, high recurrence rate, and limited treatment options [28]. e median OS among HCC patients with PVTT has been reported to be as low as 2 to 4 months [28]. Although immunotherapies, e.g., atezolizumab plus bevacizumab, provided encouraging results in the treatment of unresectable HCC when compared to sorafenib, they have not been widely used clinically [29]. e adjunctive externalbeam radiation therapy also showed potential in treating HCC patients with PVTT, but high-quality evidence of its benefits is yet to be obtained [30]. According to the Chinese guidelines for the treatment of HCC [31], TACE, systemic therapy (sorafenib or FOLFOX chemotherapy), surgical resection, and radiotherapy are recommended for the treatment of vascular invasion, whereas systemic therapy (sorafenib or FOLFOX4), TACE, and radiotherapy are recommended for the treatment of extrahepatic metastases. Sorafenib is recommended as the first-line therapy by the BCLC clinical staging system and sorafenib combined with TACE is more effective than TACE alone for patients with advanced HCC, but its survival benefit in HCC patients with PVTT was reported to be modest [7,32,33]. Considering the high cost of sorafenib treatment and its small effect, apatinib with a lower price and higher binding affinity to VEGFR-2 appears as a promising alternative for advanced HCC  Journal of Oncology 7 patients. In fact, several previous studies involving the combined treatment of TACE + apatinib reported encouraging results in patients with advanced HCC [22,23]. Nevertheless, in these studies, cases with PVTT were only a subgroup of a broader category of patients with advanced HCC. erefore, it is necessary to conduct studies to determine the efficacy and safety of the combined treatment of TACE + apatinib in HCC patients with PVTT.
To the best of our knowledge, only two studies focused on the effects of the combination of TACE and apatinib in the treatment of HCC patients with PVTT [22,34]. e study conducted by Liu assessed the efficacy and tolerability of this combined treatment for advanced HCC, but it did not include TACE alone as a control group. us, it is essential to compare the efficacy and safety between the groups of TACE + apatinib and TACE alone using a PSM analysis, which may provide more reliable results. e present study revealed that the combined treatment with TACE + apatinib significantly prolonged the median OS and TTP compared with TACE alone. e multivariate analysis further demonstrated that TACE + apatinib therapy was an independent factor in prolonging OS and TTP. Yuan and coworkers reported that combining TACE with sorafenib significantly increased the median OS for the HCC patients  Journal of Oncology with PVTT in comparison with TACE alone (OS: 13.0 vs. 6.0 months, P < 0.001) [15], while Chu and colleagues reported that the median OS of patients treated with the combination of TACE and sorafenib was 12 months [24], i.e., slightly inferior to that observed in our study. A meta-analysis reported that in the included studies, the median TTP of patients treated with the combination of TACE and sorafenib ranged from 3 to 7 months [35]. ese results revealed that the efficacy of TACEapatinib in the treatment of HCC patients with PVTT was not inferior to that of TACE-sorafenib. In our study, the side effects of apatinib were acceptable and manageable, a finding reported in many previous studies [21][22][23]. e common adverse events related to apatinib included hand-foot skin reactions, hypertension, diarrhea, fatigue, oral ulcer, headache, proteinuria, voice change, and gastrointestinal hemorrhage. ese adverse events were predominantly grade 1 or 2. In several patients, grade 3 apatinibrelated adverse events were alleviated after the dose reduction, implying that they were controllable. Generally, adverse events of apatinib in our study were similar to those reported for sorafenib [15,24].
us, TACE + apatinib is safe for HCC patients with PVTT.
To further define which subgroup of patients benefited more from the combination treatment, subgroup analysis was conducted. Except for patients with Child-Pugh class B, the efficacy of TACE + apatinib for the patients with or without extrahepatic metastases and patients with Child-Pugh class A was superior to that of TACE-alone. is result indicates that the patients with these characteristics were more suitable for the treatment with the combination of TACE and apatinib. e difference in the outcomes for the patients with Child-Pugh classes A and B revealed that liver function might affect the therapeutic impact of TACE + apatinib.
Although our study provided encouraging results, it has some limitations. First, the study was designed as a retrospective analysis, and despite performing PSM, the potential patient selection bias could not be avoided entirely. Second, the data in our study originated from one clinical center. Prospective randomized controlled trials are needed in the future to provide high-level evidence for the effectiveness and safety of TACE + apatinib for the treatment of HCC patients with PVTT.

Conclusions
In conclusion, the data on the efficacy of TACE + apatinib in HCC patients with PVTT are encouraging. e TACE + apatinib combination therapy is safe in this group of patients.

Data Availability
e data used in the study are available from the corresponding author on reasonable request.

Ethical Approval
is study was approved by the Ethics Committee of Union Hospital of Huazhong University of Science and Technology (UHCT-IEC-SOP-016-03-01).

Consent
Written informed consent was waived by this institution.

Conflicts of Interest
All authors declare that they have no competing interests.

Authors' Contributions
Tao Sun, Lei Chen, and Xuefeng Kan contributed equally to this work.